The present invention relates to methods, kits, and pharmaceutical compositions for inhibiting the proliferation of cells.
Anaplastic lymphoma kinase (ALK), a receptor tyrosine kinase in the insulin receptor superfamily, was first identified as a chromosomal rearrangement (NPM-ALK fusion gene) in anaplastic large cell lymphoma (ALCL) (Morris et al., Science 263:1281 (1994)). Alternate EML4-ALK gene translocations have been detected in a subset of non-small cell lung cancers (NSCLC), translocations with over a dozen other fusion partners have been observed, and single point mutations in ALK have been identified in a subset of neuroblastomas (Soda et al., Nature 448:561 (2007); Mossé et al., Nature 455:930 (2008); Janoueix-Lerosey et al., Nature 455:967 (2008); George et al., Nature 455:975 (2008); Webb et al., Expert Rev. Anticancer Ther. 9:331 (2009); and Chen et al., Nature 455:930 (2008)). Whereas expression of ALK is limited in normal adult human tissues, genetic studies indicate that aberrant expression of ALK or ALK fusions is a key driver in various tumor types, which highlights ALK as an important target in treating human tumors. The high sequence homology of ALK with other members of the insulin receptor superfamily presents a significant challenge in the design of ALK-selective inhibitors.
Other challenges to developing a successful therapy based on inhibiting a kinase like ALK include the existence or development of compensatory biological mechanisms, such as alternative signaling pathways that bypass or supercede ALK, ALK gene amplification or overexpression, increased drug efflux, or the development of mutations which impair binding of an inhibitor to ALK. If such mutations occur, it would be important to learn of their existence, be able to identify them in patients, identify effective inhibitors for such mutants, and treat a patient who has such a mutation with an inhibitor to target that mutant.
New diagnostic methods and therapies are needed for the detection and treatment of ALK-driven cancers, especially for those in which ALK mutations confer resistance to inhibitors of “wild-type” ALK kinases.